The overall goals of the Cancer Regulatory Networks (CRN) Program are to study regulatory networks within the cancer cell and between cancer cells and the tumor environment. The Program has three scientific themes: 1) Oncogenic and Tumor Suppressor Signaling: the analysis of signal transduction pathways that orchestrate the oncogenic phenotype; 2) Tumor Microenvironment: the study of host cells that interact with tumor cells to influence growth, the inflammatory response, and metastasis; and 3) Cancer Systems Biology: the use of model-based approaches to generate testable hypotheses about genetic drivers of cancer, to dissect and interrogate gene regulatory networks, and to identify Master Regulator genes. The latter theme was recently formulated to reflect a major HICCC strength in cancer systems biology (which is also embodied in the new Department of Systems Biology established by Columbia University in 2013). The CRN Program promotes collaboration among its members (intra-programmatic interactions) and with other HICCC members in the basic science, disease-specific and population sciences programs (inter- programmatic interactions), as well as with cancer scientists at other NCI-supported Cancer Centers nationwide. The Program provides a forum in which CRN investigators share their latest discoveries and seek translational applications of their work. The Program also stimulates research by providing investigator feedback to the HICCC Senior Leadership Team (SLT) and the HICCC Shared Resources (SRs). The Program actively seeks opportunities for clinical translation of CRN basic science discoveries, as evidenced by recent awards supporting several NCI centers of excellence to study druggable targets and drug mechanisms; including Cancer Target Discovery and Development (CTD2), Integrative Cancer Biology Programs for Cancer Systems Biology, and centers in the Library of Integrated, Network Based Cellular Signatures. The development, assembly, and interrogation of tumor regulatory models for virtually all tumor types represented in TCGA, TARGET, and COSMIC, has led to an N of 1 initiative at Columbia to study oncogene-induced dependencies that can be targeted pharmacologically on an individual patient basis. The CRN Program consists of 40 members (38 full, 2 clinical scientists) associated with nine basic science and nine clinical departments at Columbia University. The total number of cancer-related publications by the current Program members since the previous site visit is 539, with 2 1% inter-programmatic and 5% intra-programmatic publications. Of these, 37% appeared in high impact journals with impact factor >10 and 12% with an impact factor >20. During the most recent funding period, the CRN Program received funding of $17.8M (direct costs) in cancer-relevant grant support, including $7.0M (direct costs) in NCI funding.